Perspective on a Modified Developmental and Reproductive Toxicity Testing Strategy for Cancer Immunotherapy

The intent of cancer immunotherapy (CIT) is to generate and enhance T-cell responses against tumors. The tumor microenvironment establishes several inhibitory pathways that lead to suppression of the local immune response, which is permissive for tumor growth. The efficacy of different CITs, alone and in combination, stems from reinvigorating the tumor immune response via several mechanisms, including costimulatory agonists, checkpoint inhibitors, and vaccines. However, immune responses to other antigens (self and foreign) may also be enhanced, resulting in potentially undesired effects. In outbred mammalian pregnancies, the fetus expresses paternally derived alloantigens that are recognized as foreign by the maternal immune system. If unchecked or enhanced, maternal immunity to these alloantigens represents a developmental and reproductive risk and thus is a general liability for cancer immunotherapeutic molecules. We propose a tiered approach to confirm this mechanistic reproductive liability for CIT mo...